Herniated intervertebral disc is a disease attributed to protrusion of nucleus pulposus of an intervertebral disc. The protruded nucleus pulposus stimulates nerves therearound to cause symptoms including lower back pain.
Among herniated intervertebral disc, herniated intervertebral disc classified into sequestered type herniated intervertebral disc according to Macnab's classification is herniated intervertebral disc where nucleus pulposus of an intervertebral disc protrudes through the most outer layer of anulus fibrosus and posterior mediastinal ligaments to completely separate from a central intervertebral disc and migrates into the vertebral epidural space in the vertebral canals. Sequestered type herniated intervertebral disc spontaneously disappears a certain period of time. However, it causes severe pain until its spontaneous disappearance and the patients suffer from considerable pain. Thus, it has been desired to treat them so as to save them from such severe pain as soon as possible.
On the other hand, among herniated intervertebral disc, herniated intervertebral disc classified into transligamentous extrusion type herniated intervertebral disc according to Macnab's classification is herniated intervertebral disc where nucleus pulposus of an intervertebral disc protrudes through the most outer layer of anulus fibrosus and posterior mediastinal ligaments such as that in sequestered type herniated intervertebral disc but it does not separate from a central intervertebral disc. Thus, since transligamentous extrusion type herniated intervertebral disc is characterized by existence of epidurally nucleus pulposus in common with sequestered type herniated intervertebral disc, it has been desired to treat patients of transligamentous extrusion type herniated intervertebral disc with the same manner for treating patients of sequestered type herniated intervertebral disc. In the present specification, herniated intervertebral disc where nucleus pulposus is existing epidurally, such as transligamentous extrusion type herniated intervertebral disc and sequestered type herniated intervertebral disc, is generally called as "epidurally migrating herniated intervertebral discs".
For the conventional treatment of herniated intervertebral disc, intervertebral disc dissolution treating method (ID method) was developed in which proteolytic enzyme such as chymopapain or bacterial collagenase is injected into the intervertebral disc of a patient with hernia to dissolve the herniated part. Chymopapain (trade name: Chymodiactin) is commercially available as a drug.
By the above ID method using proteolytic enzyme, however, the protein portions of the surrounding structural tissue are dissolved as well as the herniated part of the spine and intervertebral disc. Thus, this method is disadvantageous in likely causing side effects such as neuroparalysis or onset of allergy.
Particularly, when the above-described proteolvtic enzyme is injected into the vertebral epidural space to dissolve nucleus pulposus migrating in the vertebral epidural space, the proteolytic enzyme dissolves not only the nucleus pulposus but also spine. Thus, such administration and treatment are not acceptable.
Recently, an attempt has been made to treat herniated intervertebral disc by injecting chondroitinase ABC or chondroitinase AC into the intervertebral disc. Thus, it has been expected to use these enzymes as a therapeutic drug for herniated intervertebral disc (U.S. Pat. No. 4,696,816 Specification, Clinical Orthopaedics, 253, 301-308 (1990)).
For example, chondroitinase ABC [EC 4.2.2.4] is an enzyme that degrades glycosaminoglycan to unsaturated oligosaccharide and unsaturated disaccharide. It strongly catalyzes degradation of chondroitin sulfate A derived from mammalian cartilage, chondroitin sulfate C derived from cartilage of shark, and chondroitin sulfate B which is called dermatan sulfate derived from mammalian skin, whereas it weakly catalyzes degradation of hyaluronan.
Chondroitinase as described above has been conventionally directly injected into the intervertebral disc. However, such administration is not effective for treating epidurally migrating herniated intervertebral disc. This is because injection of chondroitinase into the intervertebral disc cannot dissolve nucleus pulposus migrating in the vertebral epidural space.
Any composition for administration of a glycosaminoglycan degrading enzyme such as chondroitinase to the vertebral epidural space has not been known so far. Also, any therapeutic agent for epidurally migrating herniated intervertebral disc comprising a glycosaminoglycan degrading enzyme like chondroitinase as an active ingredient has not been known.
Therefore, it has been desired to develop a pharmaceutical composition and an agent that can be used for treating epidurally migrating herniated intervertebral disc.